This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of musculoskeletal frailty including osteoporosis.
Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body:
1. Increased rate of protein synthesis in substantially all cells of the body;
2. Decreased rate of carbohydrate utilization in cells of the body; and
3. Increased mobilization of free fatty acids and use of fatty acids for energy.
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or nasal spray.
Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion, which include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
Obesity is a major risk factor for diabetes, and a large fraction of NIDDM patients are obese. Both conditions are characterized by elevated circulating insulin levels and suppressed GH levels. GH treatment of GH-deficient adults (Jorgensen, J. O. L., et al., Lancet 1:1221 (1989)), obese women (Richelsen, B., et al., Am J Physiol, 266:E211 (1994)) and elderly men (Rudman, D., et al, Horm Res 36 (Suppl 1):73 (1991)) has been shown to produce increases in lean body, hepatic and muscle mass while decreasing fat mass. Thus, GH therapy for obesity would seem attractive except for the diabetogenic effects of GH.
An alternative to exogenous GH administration is therapy that stimulates endogenous GH secretion. It has been shown that a substantial pituitary reserve of GH is present in pituitary-intact GH-deficient patients and the elderly so that decreased serum GH levels are due to hyposecretion.
Hyposecretion of GH in several clinical settings (obesity, aging, glucocorticoid suppression) is relatively resistant to stimulation by GHRH (Gertz, B. J., et al., J Clin Endocrinol Metab, 79:745 (1994); Arvat, E., et al., J Clin Endocrinol Metab, 79:1440 (1994); Maccario, M., et al., Metabolism, 44:134 (1995)). In contrast, administration of a growth hormone releasing peptide (GHRP) or combined administration of growth hormone releasing hormone (GHRH) and a GHRP in these patients can elicit a robust GH response (Aloi, J. A., et al., J Clin Endocrinol Metab, 79:943; (1994)). Single dose studies of GHRPs have demonstrated the absence of an acute effect on circulating insulin or glucose levels. Insulin and glucose have generally not been monitored in chronic studies except to document the absence of unfavorable changes (Jacks, T., et al., J Endocrinol. 143:399 (1993)).
Prior to the present invention, the use of GHRPs or GHRP mimetics to improve glycemic control has not specifically been explored. The method of treating insulin resistance in a mammal comprising the administration of a compound of Formula I of this invention is practiced preferentially in patients who have a functional hypothalamic-pituitary axis capable of GH secretory responses to GHRPs and who have pancreatic beta-cells capable of secreting insulin.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GHRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones, are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low.
International Patent Application Publication No. WO 94/13696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds described therein are of the general structure shown below: 
International Patent Application Publication No. WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure: 
where L is 
The compounds of WO 94/11012 and WO 94/13696 are disclosed to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.
International Patent Application Publication No. WO 97/09060 discloses the use of growth hormone releasing hormone or a functional analog thereof in the treatment of insulin resistance in mammals.
International Patent Application Publication No. WO98/10653 discloses compounds of the formula: 
wherein the variables are defined as set forth therein.
International Patent Application Publication No. WO97/24369 discloses growth hormone secretagogue compounds of the formula: 
wherein R6 is a bond or is 
and the remaining variables are as defined as set forth therein.
This invention is directed to compounds of the Formula l: 
or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug,
wherein:
HET is a heterocyclic moiety selected from the group consisting of 
xe2x80x83d is 0, 1 or 2;
e is 1 or 2;
f is 0 or 1;
n and w are 0, 1 or 2, provided that n and w cannot both be 0 at the same time;
Y2 is oxygen or sulfur;
A is a divalent radical, where the left hand side of the radical as shown below is connected to Cxe2x80x3 and the right hand side of the radical as shown below is connected to Cxe2x80x2, selected from the group consisting of
xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x95x90C(R11)xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R11)xe2x95x90Nxe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(R11)xe2x95x90Nxe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94N(R12)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR12xe2x80x94, xe2x80x94Nxe2x95x90C(R11)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94 and xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94;
Q is a covalent bond or CH2;
W is CH or N;
X is CR9R10, Cxe2x95x90CH2 or Cxe2x95x90O;
Y is CR9R10, O or NR2;
Z is Cxe2x95x90O, Cxe2x95x90S or S(O)2;
G1 is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl, xe2x80x94CONH2, xe2x80x94(C1-C4)alkyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkoxy optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkylthio, phenoxy, xe2x80x94COO(C1-C4)alkyl, N,N-di-(C1-C4)alkylamino, xe2x80x94(C2-C6)alkenyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C2-C6)alkynyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C3-C6)cycloalkyl optionally independently substituted with one or more (C1-C4)alkyl groups, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkylamino carbonyl or di-(C1-C4)alkylamino carbonyl;
G2 and G3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94(C1-C4)alkyl optionally independently substituted with one to three halogens and xe2x80x94(C1-C4)alkoxy optionally independently substituted with one to three halogens;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups;
R1A is selected from the group consisting of hydrogen, F, Cl, Br, I, (C1-C6)alkyl, phenyl(C1-C3)alkyl, pyridyl(C1-C3)alkyl, thiazolyl(C1-C3)alkyl and thienyl(C1-C3)alkyl, provided that R1A is not F, Cl, Br or I when a heteroatom is vicinal to Cxe2x80x3;
R2, for each occurrence, is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halogens;
R3 is selected from the group consisting of A1, (C1-C10)alkyl, xe2x80x94(C1-C6)alkyl-A1, xe2x80x94(C1-C6)alkyl-(C3-C7)cycloalkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C0-C5)alkyl-A1 and xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl-(C3-C7)cycloalkyl;
where the alkyl groups in the definition of R3 are optionally substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1, 2, 3, 4 or 5 independently selected halogens or 1, 2 or 3 independently selected xe2x80x94OX3 groups;
X1 is O, S(O)m, xe2x80x94N(X2)C(O)xe2x80x94, xe2x80x94C(O)N(X2)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94CX2xe2x95x90CX2xe2x80x94, xe2x80x94N(X2)C(O)Oxe2x80x94, xe2x80x94OC(O)N(X2)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring;
R6 is xe2x80x94(CRaRb)axe2x80x94Exe2x80x94(CRaRb)bxe2x80x94, where the xe2x80x94(CRaRb)axe2x80x94 group is attached to the carbonyl carbon of the amide group of the compound of formula I and the xe2x80x94(CRaRb)b group is attached to the terminal nitrogen atom of the compound of formula I;
E is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or an aromatic moiety selected from 
xe2x80x83said aromatic moiety in the definition of E optionally substituted with up to three halo, hydroxy, xe2x80x94N(Rc)(Rc), (C1-C6)alkyl or (C1-C6)alkoxy;
Ra and Rb are, for each occurrence, independently hydrogen, (C1-C6)alkyl, trifluoromethyl, phenyl or monosubstituted (C1-C6)alkyl where the substituents are imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, xe2x80x94ORc, S(O)mRc, C(O)ORc, (C3-C7)cycloalkyl, xe2x80x94N(Rc)(Rc), xe2x80x94C(O)N(Rc)(Rc), or Ra or Rb may independently be joined to one or both of R7 or E (where E is other than O, S or xe2x80x94CHxe2x95x90CHxe2x80x94) to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the Ra or Rb and the R7 or E group, wherein the bridge contains 1 to 8 carbon atoms; or Ra and Rb may be joined to one another to form a (C3-C7)cycloalkyl;
Rc, for each occurrence, is independently hydrogen or (C1-C6)alkyl;
a and b are independently 0, 1, 2 or 3, with the proviso that if E is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, y is other than 0 or 1 and with the further proviso that if E is xe2x80x94CHxe2x95x90CHxe2x80x94, y is other than 0;
R7 and R8 are each independently hydrogen or optionally substituted (C1-C6)alkyl;
where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, xe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy groups, 1 to 3 xe2x80x94Oxe2x80x94C(O)(C1-C10)alkyl groups or 1 to 3 (C1-C6)alkoxy groups; or
R7 and R8 can be taken together to form xe2x80x94(CH2)rxe2x80x94Lxe2x80x94(CH2)rxe2x80x94;
where L is C(X2)(X2), S(O)m or N(X2);
R9 and R10 are each independently selected from the group consisting of hydrogen, fluoro, hydroxy and (C1-C5)alkyl optionally independently substituted with 1-5 halogens;
R11 is selected from the group consisting of (C1-C5)alkyl and phenyl optionally substituted with 1-3 substituents each independently selected from the group consisting of (C1-C5)alkyl, halo and (C1-C5)alkoxy;
R12 is selected from the group consisting of (C1-C5)alkylsulfonyl, (C1-C5)alkanoyl and (C1-C5)alkyl where the alkyl portion is optionally independently substituted by 1-5 halogens;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11, for each occurrence, is independently hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12, for each occurrence, is independently hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2;
with the proviso that:
X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12.
A preferred group of compounds, designated the A Group, comprises those compounds having the Formula I shown above or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs,
wherein
X4 is hydrogen;
R4 is hydrogen or methyl;
R7 is hydrogen or (C1-C3)alkyl; and
R8 is hydrogen or (C1-C3)alkyl optionally substituted with up to two hydroxyl groups.
A preferred group of compounds within the A Group, designated the B Group, comprises those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs,
wherein
Het is 
xe2x80x83R1 is A1xe2x80x94(CH2)t, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl or (C1-C10)alkyl;
where A1 in the definition of R1 is optionally substituted with up to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethoxy, difluoromethoxy and trifluoromethyl;
the cycloalkyl and alkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or up to 3 fluoro;
Y2 is O; and
R2 is hydrogen, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, phenyl or (C1-C8)alkyl where the (C1-C8)alkyl group is optionally substituted with hydroxy, trifluoromethyl or up to 3 halogen.
A preferred group of compounds within the B Group, designated the C Group, comprises those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein n and w are each 1; f is 0; R2 is H, methyl, ethyl or trifluoroethyl and R1 is phenyl-CH2xe2x80x94, pyridyl-CH2xe2x80x94 or thiazolyl-CH2.
A preferred group of compounds within the C Group, designated the D Group, comprises those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R7 and R8 are each hydrogen; and R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or naphthyl-CH2; said phenyl being optionally substituted with up to three fluoro, chloro.
A preferred compound within the D Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R1 is phenyl-CH2xe2x80x94, R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each hydrogen; a is 0; b is 1; and E is vinylene.
Another preferred compound within the D Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R1 is phenyl-CH2xe2x80x94, R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra is methyl; Rb is hydrogen; a is 0; b is 1; and E is vinylene.
Another preferred compound within the D Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R1 is phenyl-CH2xe2x80x94, R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each methyl; a is 0; b is 1; and E is vinylene.
Another preferred compound within the D Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R1 is phenyl-CH2; R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each hydrogen; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the D Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra is methyl; Rb is hydrogen; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the D Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each methyl; a is 0; b is 1; and E is metaphenylene.
A preferred group of compounds within the D Group are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, selected from 4-amino-but-2-enoic acid (2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-amide; 4-amino-pent-2-enoic acid (2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexaydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-amide; 4-amino-4-methyl-pent-2-enoic acid (2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-amide; 3-aminomethyl-N-(2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-benzamide; 3-(1-amino-ethyl)-N-(2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-benzamide; and 3-(1-amino-1-methyl-ethyl)-N-(2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-benzamide.
Another preferred group of compounds within the B Group, designated the E Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein n and w are each 1; f is 0; R2 is hydrogen; R3 is Phxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; R7 and R8 are each hydrogen; and R1 is phenyl-CH2xe2x80x94.
A particularly preferred compound within the E Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each methyl; a is 0; b is 1; and E is metaphenylene.
Another particularly preferred compound within the E Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, which is 3-(1-amino-1-methyl-ethyl)-N-(2-(3a-benzyl-03-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl)-benzamide.
Another preferred group of compounds within the C Group, designated the F Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R7 and R8 are each hydrogen; and R3is 3-indolyl-methyl.
A preferred compound within the F Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each methyl; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the F Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, which is 3-(1-amino-1-methyl-ethyl)-N-(2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl)-benzamide.
Another preferred group within the B Group, designated the G Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein n and w are each 1; f is 0; R2 is 2,2,2-trifluoroethyl; and R1 is 2-pyridylmethyl.
A preferred group of compounds within the G Group, designated the H Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, R7 and R8 are each hydrogen; and R3 is 2,4-difluorobenzyloxymethyl.
A particularly preferred compound within the H Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each hydrogen; a is 0; b is 1; and E is metaphenylene.
Another particularly preferred compound within the H Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, which is 3-(1-amino-1-methyl-ethyl)-N-(2-(3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(2,4-difluorobenzyloxymethyl)-2-oxo-ethyl)-benzamide.
Another particularly preferred group of compounds within the A Group, designated the I Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs,
wherein
Het is 
R1 is xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl or (C1-C10)alkyl;
where A1 in the definition of R1 is optionally substituted with up to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethoxy, difluoromethoxy and trifluoromethyl; and
the cycloalkyl and alkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or up to 3 fluoro.
A preferred group of compounds within the I Group, designated the J Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein Z is Cxe2x95x90O; Q is a covalent bond; X is Cxe2x95x90O; R2 is H, methyl, ethyl or trifluoroethyl; R1 is phenyl-CH2xe2x80x94, pyridyl-CH2xe2x80x94 or thiazolyl-CH2; and Y is NR2.
A preferred group of compounds within the J Group, designated the K Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein Z is Cxe2x95x90O; R1 is A1xe2x80x94CH2xe2x80x94, where A1 in the definition of R1 is phenyl or pyridyl where said phenyl or pyridyl is optionally substituted with up to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl; and R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, pyridyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-(CH2)3xe2x80x94, 3-indolyl-CH2xe2x80x94, alpha-naphthyl(C1-C4)alkyl or thiazolyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, where the aryl portion of the groups defined for R3 is optionally substituted with up to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl.
A preferred group of compounds within the K Group, designated the L Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R2 is hydrogen or (C1-C3)alkyl where the alkyl group is optionally substituted with up to three fluoro groups.
A preferred group of compounds within the L Group, designated the M Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2 or phenyl-(CH2)3xe2x80x94, where the phenyl in the definition of R3 is optionally substituted with up to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl.
A preferred group of compounds within the M Group, designated the N Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R1 is CH2xe2x80x94A1 where A1 in the definition of R1 is phenyl, 2-pyridyl or 3-pyridyl optionally substituted with up to three fluoro or chloro groups; R2 is methyl or ethyl, said ethyl being optionally substituted with up to three fluoro groups; and R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, where the phenyl group is optionally substituted with up to three fluoro or chloro groups or up to two trifluoromethyl groups.
A preferred group of compounds within the N Group, designated the O Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R1 is 2-pyridylmethyl; R2 is 2,2,2-trifluroethyl; R3 is 2,4-difluorophenylmethyloxymethyl; and R4, X4, R7 and R8 are each hydrogen.
A preferred compound within the O Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each hydrogen; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the O Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra is methyl; Rb is hydrogen; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the O Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each methyl; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the O Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each hydrogen; a is 0; b is 1; and E is vinylene.
Another preferred compound within the O Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra is methyl; Rb is hydrogen; a is 0; b is 1; and E is vinylene.
Another preferred compound within the O Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each methyl; a is 0; b is 1; and E is vinylene.
A preferred group of compounds within the O Group are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, selected from 3-aminomethyl-N-(1-(2,4-difluoro-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-benzamide; 3-(1-amino-ethyl)-N-(1-(2,4-difluoro-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-20-oxo-ethyl)-benzamide; 3-(1-amino-1-methyl)-N-(1-(2,4-difluoro-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-benzamide; 4-amino-but-2-enoic acid (1-(2,4-difluoro-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-amide; 4-amino-pent-2-enoic acid (1-(2,4-difluoro-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-amide; and 4-amino-4-methyl-pent-2-enoic acid (1-(2,4-difluoro-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-amide.
Another preferred group of compounds within the N Group, designated the P Group, are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, wherein R1 is 2-pyridylmethyl; R2 is 2,2,2-trifluroethyl; R3 is phenylmethyloxymethyl; and R4, X4, R7 and R8 are each hydrogen.
A preferred compound within the P Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each hydrogen; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the P Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra is methyl; Rb is hydrogen; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the P Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein Ra and Rb are each methyl; a is 0; b is 1; and E is metaphenylene.
Another preferred compound within the P Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each hydrogen; a is 0; b is 1; and E is vinylene.
Another preferred compound within the P Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra is methyl; Rb is hydrogen; a is 0; b is 1; and E is vinylene.
Another preferred compound within the P Group is the compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein R2 is methyl; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94; Ra and Rb are each methyl; a is 0; b is 1; and E is vinylene.
A preferred group of compounds within the P Group are those compounds or stereoisomeric mixtures thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers thereof, or prodrugs of such compounds, mixtures or isomers thereof, or pharmaceutically acceptable salts of the compounds, mixtures, isomers or prodrugs, selected from 3-aminomethyl-N-(2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl)-benzamide; 3-(1-amino-ethyl)-N-(benzyloxymethyl-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-benzamide; 3-(1-amino-1-methyl-ethyl)-N-(benzyloxymethyl-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-benzamide; 4-amino-but-2-enoic acid (1-benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-amide; 4-amino-pent-2-enoic acid (1-(benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-amide; and 4-amino-4-methyl-pent-2-enoic acid (1-(benzyloxymethyl)-2-(1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-amide.
This invention is also directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to methods for treating or preventing musculoskeletal frailty in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within the above method is a method wherein osteoporosis is treated.
This invention is also directed to methods for increasing IGF-1 levels in mammal deficient in IGF-1 comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method, designated Method A, for treating or preventing a growth hormone mediated disease or condition in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method A, designated Method B, is a method wherein the disease or condition is diabetes, congestive heart failure, obesity, frailty associated with aging or frailty associated with obesity.
A preferred method within Method B is a method wherein the disease or condition is congestive heart failure.
Another preferred method within Method B is a method wherein the disease or condition is frailty associated with aging.
This invention is also directed to a method, designated Method C, for accelerating bone fracture repair in a mammal, attenuating protein catabolic response after a major operation in a mammal, reducing cachexia and protein loss due to chronic illness in a mammal, accelerating wound healing in a mammal, or accelerating the recovery of burn patients or patients having undergone major surgery comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method C is a method for accelerating the recovery of patients having undergone major surgery.
Another preferred method within Method C is a method for accelerating bone fracture repair.
This invention is also directed to a method for improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method, designated Method D, for the treatment or prevention of musculoskeletal frailty in a mammal comprising administering to said mammal a therapeutically effective amount of a bisphosphonate and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method D is wherein osteoporosis is treated in a mammal.
Another preferred method within Method D is wherein said bisphosphonate is alendronate.
Another preferred method within Method D is wherein said bisphosphonate is ibandronate.
This invention is also directed to a method, designated Method E, for the treatment or prevention of musculoskeletal frailty in a mammal comprising administering to said mammal a therapeutically effective amount of estrogen or Premarin(copyright) and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method E is wherein osteoporosis is treated in a mammal.
This invention is also directed to a method, designated Method F, for the treatment of musculoskeletal frailty in a mammal comprising administering to said mammal a therapeutically effective amount of calcitonin and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method F is wherein osteoporosis is treated in a mammal.
This invention is also directed to a method, designated Method G, for the treatment of musculoskeletal frailty in a mammal comprising administering to said mammal a therapeutically effective amount of a selective estrogen receptor modulator (SERM) and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method G is wherein said SERM is tamoxifen, droloxifene, raloxifene or idoxifene.
Another preferred method within Method G is wherein said SERM is cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene; 1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline.
This invention is also directed to a method for enhancing growth and improving carcass quality of an animal other than a human comprising administering to said animal an effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method for enhancing feed efficiency in an animal other than a human comprising administering to said animal an effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method for increasing milk production in a female mammal comprising administering to said female mammal an effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method for increasing piglet number, increasing pregnancy rate in a sow, increasing viability of a piglet, increasing weight of a piglet or increasing muscle fiber size in a piglet comprising administering to said sow or piglet an effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method for increasing muscle mass in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method for promoting growth in a growth hormone deficient child comprising administering to said growth hormone deficient child a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method, designated Method H, for the treatment or prevention of diabetes, congestive heart failure, obesity, frailty associated with aging or frailty associated with obesity in a mammal comprising administering to said mammal a therapeutically effective amount of a functional somatostatin antagonist and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method H is wherein said functional somatostatin antagonist is an alpha-2 adrenergic agonist and the mammal is a dog, cat or horse.
Another preferred method within Method H is wherein said alpha-2 adrenergic agonist is clonidine, xylazine or medetomidine.
This invention is also directed to a method, designated Method I, for treating insulin resistance in a mammal comprising administering to said mammal an effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
A preferred method within Method I is wherein said mammal is suffering from type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance or an insulin resistant syndrome.
Another preferred method within Method I is wherein said mammal is suffering from insulin resistance is associated with obesity or old age.
This invention is also directed to a method for increasing the endogenous production or release of growth hormone in a mammal comprising administering a therapeutically effective amount of a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug and a growth hormone secretagogue selected from the group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug; a bisphosphonate and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug; estrogen or Premarin(copyright) and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a pharmaceutical composition as set forth in the immediately preceding paragraph further comprising progesterone.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, calcitonin and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, an alpha-2 adrenergic agonist and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a pharmaceutical composition as set forth in the immediately preceding paragraph wherein said alpha-2 adrenergic agonist is clonidine, xylazine or medetomidine.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, a growth hormone secretagogue selected from the group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof, and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, a 3 adrenergic receptor agonist and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a pharmaceutical composition as set forth in the immediately preceding paragraph wherein said (3 adrenergic receptor agonist is (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid.
This invention is also directed to a method for increasing levels of endogenous growth hormone in a mammal comprising administering to said mammal a therapeutically effective amount of a functional somatostatin antagonist and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a method for treating obesity and/or improving lean meat to fat ratio in a mammal comprising administering to said mammal a therapeutically effective amount of a xcex23 adrenergic receptor agonist and a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, a selective estrogen receptor modulator (SERM) and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a pharmaceutical composition comprising a compound of Formula I or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, a functional somatostatin antagonist and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. a growth hormone secretagogue selected from the group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. a selective estrogen receptor modulator (SERM) and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. calcitonin and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. a functional somatostatin antagonist and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. a bisphosphonate and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. estrogen or Premarin(copyright) and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to a kit comprising:
a. a compound of claim 1 and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. a xcex23 adrenergic receptor agonist and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. a container.